Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Eighty families with documented CDKN2A mutations and multiple cases of cutaneous melanoma from The Melanoma Genetics Consortium were analyzed to examine penetrance. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval = 0.12-0.62) by age 50 years and 0.67 (95% confidence interval =0.31-0.96) by age 80 years. There was a statistically significant association with residing in a region with a high incidence of melanoma. By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years, it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Examination of children with medulloblastoma revealed that a subset carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the sonic hedgehog (SHH) signaling pathway. SUFU is a newly identified tumor suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism. Analyses of the data from a case-control study of ovarian cancer in Israel of the Jewish population revealed that oophorectomy and other gynecology surgery appeared protective among both carriers and noncarriers of founder BRCA1/2 mutations. As a follow-up to a recently completed DCEG comprehensive case-control study of adults with brain tumors, a family-based study of the parents, siblings and adult children of the 480 eligible glioma cases is being conducted. Relatives are interviewed about personal and family medical history and other risk factors and are asked to provide buccal cells as a source of DNA. The relatives will be used as controls for the glioma cases in association studies and in analyses to evaluate the roles of genetic susceptibility and environmental exposures on the risk of gliomas and etiologically related tumors. A case-control study of 183 incident melanoma cases and 179 controls conducted in northeastern Italy identified the strongest risk factors for non-familial melanoma and determined how the combinations of these factors contributed to melanoma risk in Mediterranean populations. Presence of dysplastic nevi, low propensity to tan, light eye and light skin color were all highly associated with melanoma risk after adjustment for age, gender, and pigmentation characteristics. DNA repair capacity was an important modifier of melanoma risk in the presence of other strong risk factors, such as low propensity to tan and presence of dysplastic nevi. Constitutive skin color and UV sensitivity were assessed by Minolta CR-300 colorimeter and minimal erythema dose (MED), respectively. Melanoma risk increased with skin brightness and MED, particularly in subjects with the highest levels of sun exposure. Linked data from cancer, population, and hospital discharge registries have been obtained from collaborators in Denmark and Sweden which includes cases of lymphoproliferative (LP) cancers including Hodgkin's disease, Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia, and Multiple Myeloma, matched controls, and first degree relatives of cases and controls. Hypotheses to examine increased risks of LP cancers and autoimmune disorders among relatives of cases will be tested.